In the United States, according to statistical data published in 1999 by Landis et al. (CA Cancer J. Clin. 49:8-31 (1999)), prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer death, following lung cancer, in men. These results are not specific to the United States as they characterize all western countries. In addition incidence for this cancer is rising rapidly in most countries including low-risk populations, namely populations from Asian countries (Hsing et al., Int. J. Cancer 85:60-67 (2000)).
There is at present no effective treatment available for patients with advanced and/or hormone-insensitive prostate cancer. Therapeutic modalities for advanced prostate cancer are limited to drugs with considerable toxicity.
As the proliferation rate is low in these cancers, many cytotoxic agents are ineffective (Millikan, Semin. Oncol. 26(2):185-191 (1999)). Thus there is an urgent need to develop new approaches to treat patients with progressive prostate cancer. For example, gene therapy can be done using prostate-specific gene promoters linked to genes that suppress tumor cell growth, induce apoptosis and/or kill tumor cells (Taneja et al., Cancer Surv. 23:247-266 (1995); and Boulikas, Anticancer Res. 17:1471-1505 (1997)). The promoter sequences responsible for the prostate specific expression of several genes have been cloned and the unraveling of their transcriptional regulation is ongoing. The PSA gene promoter has been most extensively studied and revealed the existence of a proximal prostate-specific promoter with an upstream prostate-specific enhancer. Both sequences are required for high, androgen-regulated activation of PSA expression (Schuur et al., J. Biol. Chem. 271:7043-7051 (1996); Cleutjens et al., Mol. Endocrinol. 11:148-161 (1997); Cleutjens et al., Mol. Endocrinol. 11:1256-1265 (1997); Pang et al., Cancer Res. 57:495-499 (1997); and Wei et al., Proc. Natl. Acad. Sci. USA 94:6369-6374 (1997)). Using the PSA enhancer-promoter linked up to the HSV-tk gene, encoding a prodrug-converting enzyme and delivered by the human adenovirus into prostatic tumor cells growing subcutaneously in nude mice, it has been shown that prostate tumor cell growth was significantly suppressed and that the life span of the animals was prolonged (Gotoh et al., J. Urol. 160:220-229 (1998); and Martiniello-Wilks et al., Hum. Gene Ther. 9(11):1617-1626 (1998)). This proof of principle opens the way for application of promoter-based gene therapy for prostate cancer patients.
A new candidate marker for prostate cancer was discovered a few years ago by differential display analysis intended to highlight genes associated with prostate cancer development. This new gene was named PCA3 and also DD3 (Bussemakers, PCT/CA98/00346, published as WO 98/45420 (1998), Schalken, Eur. Urol. 34(suppl. 3):3-6 (1998), Bussemakers et al., Cancer Res. 59:5975-5979 (1999) and Bussemakers, Eur. Urol. 35:408-412 (1999)). PCA3dd3 is located on chromosome 9 and more precisely to region 9q21-22. It consists of four exons, which give rise, by both alternative splicing and alternative poly-adenylation, to differently sized transcripts. By RT-PCR, PCA3dd3 expression was found to be limited to the prostate tissue and absent in all other tissues tested, including testis, seminal vesicle, ovary, placenta and bladder. In addition northern blot analysis showed that PCA3dd3 is highly expressed in the vast majority of prostate cancer examined (47 out of 50) whereas no or very low expression is detected in BPH or normal prostate cells from the same patients. Of note, there is at least a 20-fold over-expression of PCA3dd3 in prostate carcinoma in comparison to normal or BPH tissues. PCA3dd3 expression seems to increase with tumor grade and is detected in metastatic lesions.
There thus remains a need to identify the promoter responsible for regulation and expression of PCA3dd3. There also remains a need to provide regulatory sequences which are prostate cancer tissue specific and to use such sequences to diagnose, prevent or treat prostate cancer.
The present invention seeks to meet these and other needs.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.